Inhibitors of cholesterol biosynthesis. 1. trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones, a novel series of HMG-CoA reductase inhibitors. 1. Effects of structural modifications at the 2- and 5-positions of the pyrrole nucleus.
A novel series of trans-6-(2-pyrrol-1-ylethyl)-4-hydroxypyran-2-ones and their dihydroxy acid derivatives were prepared and evaluated for their ability to inhibit the enzyme HMG-CoA reductase in vitro. A systematic study of substitution at the 2- and 5-positions of the pyrrole ring revealed that optimum potency was realized with the 2-(4-fluorophenyl)-5-isopropyl derivative 8x, which possessed 30% of the in vitro activity of the potent fungal metabolite compactin (I). A molecular modeling analysis led to the description of a pharmacophore model characterized by (A) length limits of 5.9 and 3.3 A for the 2- and 5-substituents, respectively, as well as an overall width limit of 10.6 A across the pyrrole ring from the 2- to the 5-substituent and (B) an orientation of the ethyl(ene) bridge to the 4-hydroxypyran-2-one ring nearly perpendicular to the planes of the parent pyrrole, hexahydronaphthalene, and phenyl rings of the structures examined (Figure 3, theta = 80-110 degrees). Attempts to more closely mimic compactin's polar isobutyric ester side chain with the synthesis of 2-phenylpyrroles containing polar phenyl substituents resulted in analogues with equal or slightly reduced potencies when compared to the 2-[(unsubstituted or 4-fluoro)phenyl]pyrroles, supporting the hypothesis that inhibitory potency is relatively insensitive to side-chain polarity or charge distribution in this area.
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Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Ortwine
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Hoefle
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Stratton
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Sliskovic
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Wilson
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Newton
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D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002627:Chemistry, Physical; D002784:Cholesterol / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D008099:Liver / Q000201:enzymology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D011714:Pyrans; D011758:Pyrroles; C012258:mevastatin; D002784:Cholesterol; D008148:Lovastatin